PROJECT SUMMARY The stress response consists of stereotyped physiological and behavioral programs that promote survival or enhanced performance during threatening or challenging situations. Stress is beneficial because it allows for a heightened response to the stressor; however, excessive stress is detrimental and can lead to or exacerbate psychiatric illnesses, such as anxiety, depression and schizophrenia. It is important to understand how the brain reacts to stress and regulates the stress response so that these pathways can be therapeutically targeted. The hippocampus is a brain structure that is known to be involved in learning and memory, but it also plays a role in regulation of stress and emotion, and is altered in these stress-related psychiatric illnesses in both humans and animal models. One component of the hippocampus that is sensitive to stress is the dentate gyrus (DG). The DG contains the highest density of stress hormone receptors in the hippocampal region and, moreover, in the entire brain. Additionally, the DG undergoes anatomical and functional changes in response to stress. The DG has been shown to be activated by stress and to regulate the stress response, but the mechanisms by which it does so are unknown. My project seeks to identify the neuronal populations in the DG that perform these functions. The principal cells of the dentate gyrus are granule cells, which reside in a distinct granule cell layer. These DG granule cells are activated by many experiences, including exploration, novelty, stress, and arousal. To understand how the dentate reacts to stress, I will characterize the DG neuronal populations activated by several types of stress. Additionally, I will use optogenetics to activate populations of DG granule cells to elucidate their effect on the hormonal and behavioral response to stress. The hippocampus is altered in many psychiatric illnesses in which stress plays a causal role. Understanding the hippocampal cells and circuits involved in regulation of stress may lead to the identification of potential cellular or circuit-based targets that can be therapeutically manipulated to alter stress regulation or to decrease the negative effects of stress on the brain, and thus, the contribution of stress to mental illness.